Liang Q, Carlson E C, Borgerding A J, Epstein P N
Department of Pharmacology and Toxicology, University of North Dakota, Grand Forks, North Dakota 58203, USA.
J Pharmacol Exp Ther. 1999 Nov;291(2):766-72.
Chronic alcohol consumption produces alcoholic heart muscle disease (AHMD), a prevalent form of congestive heart failure. Several hypotheses have been proposed to explain the damaging effects of alcohol on the heart, but neither the mechanism nor the ultimate toxin has been established. In this study, we use transgenic overexpression of alcohol dehydrogenase to elevate cardiac exposure to acetaldehyde, the major and most reactive metabolite of alcohol. Overexpression of alcohol dehydrogenase by 40-fold produced no detectable deleterious effects to the heart in the absence of alcohol. In the presence of alcohol, transgenic hearts contained 4-fold higher acetaldehyde than control hearts. Chronic alcohol exposure produced many changes similar to AHMD in transgenic hearts. Compared with control hearts, these pathological changes occurred more rapidly and to a greater extent: alcohol-exposed transgenic hearts were almost twice as large as control hearts. They demonstrated ultrastructural damage consistent with AHMD and had much lower contractility than alcohol-exposed control hearts. In addition, the transgenic hearts showed greater changes in mRNA expression for alpha-skeletal actin and atrial natriuretic factor than alcohol-exposed control hearts. Alterations in NAD(+)/NADH levels were insufficient to account for such severe damage in cardiomyopathic hearts. The increased damage produced in transgenic hearts suggests an important role for acetaldehyde in AHMD.
长期饮酒会引发酒精性心肌病（AHMD），这是充血性心力衰竭的一种常见形式。人们提出了几种假说来解释酒精对心脏的损害作用，但损害机制和最终毒素都尚未明确。在本研究中，我们通过转基因过表达乙醇脱氢酶来增加心脏对乙醛（酒精的主要且反应性最强的代谢产物）的暴露。在无酒精的情况下，乙醇脱氢酶过表达40倍对心脏未产生可检测到的有害影响。在有酒精存在时，转基因心脏中的乙醛含量比对照心脏高4倍。长期酒精暴露在转基因心脏中产生了许多与酒精性心肌病相似的变化。与对照心脏相比，这些病理变化出现得更快且程度更严重：暴露于酒精的转基因心脏几乎是对照心脏的两倍大。它们表现出与酒精性心肌病一致的超微结构损伤，并且收缩性比暴露于酒精的对照心脏低得多。此外，转基因心脏中α-骨骼肌动蛋白和心钠素的mRNA表达变化比暴露于酒精的对照心脏更大。NAD(+)/NADH水平的改变不足以解释心肌病心脏中的如此严重损伤。转基因心脏中产生的更严重损伤表明乙醛在酒精性心肌病中起重要作用。
